Combination estrogen-progestogen therapy for postmenopausal women has become increasingly popular since the mid-1970s. Early on, clinicians widely believed that, in addition to reducing the risk of endometrial cancer associated with unopposed estrogen therapy, such therapy would reduce the risk of breast cancer. It was assumed that progestogens had an "anti-estrogen" effect on breast tissue comparable to that on the endometrium, with the results of a large prospective study of women receiving various modes of therapy widely quoted as supporting this view. However, the finding of an increased risk of breast cancer associated with combination oral contraceptive therapy given around the time of menopause and the observation that breast tissue mitotic activity peaks during the luteal phase of the menstrual cycle suggest estrogen-progestogen therapy may actually increase breast cancer risk in postmenopausal women. Experimental data support this notion, as does suggestive but inadequate data on use of progestogen-only contraceptives. One prospective epidemiologic study of combination therapy and breast cancer also suggests an increased risk but the number of cases was small. To determine the effect on breast cancer risk of combination estrogen-progestogen hormonal replacement therapy as well as of unopposed estrogen replacement therapy, we have been conducting a large case-control study. Preliminary analysis from 1355 cases and 884 controls indicate that unopposed estrogen therapy moderately increases breast cancer risk overall, but in a duration and dose-related fashion. The addition of a progestogen appears to enhance these estrogen-related effects and leads to a further increase in breast cancer risk. We wish to expand this study to address more adequately duration and latency effects, the possible interaction between use of hormone replacement therapy and other breast cancer risk factors, and to confidently assess differences in risk levels with use of combination versus unopposed replacement therapy. Breast cancer patients are English- or Spanish-speaking women aged 55 and over, of all races except Asian, born in 1923 or later, and identified by our population-based tumor registry over a six year period. Controls are individually matched to cases by age (+3 years), race and neighborhood of residence. A structured interview form supplemented by a comprehensive manual containing color photographs of all types of estrogen and progestogen pills is employed for the in-person interviews. Validation of hormone therapy is accomplished by a review of physician records. The 3000 case-control pairs to be interviewed will allow for the evaluation of the effects of estrogen and estrogen- progestogen therapy on breast cancer risk in the presence of possible confounding variables, such as age at and type of menopause and weight, and for testing for interactions between hormone therapy and other breast cancer risk factors, such as benign breast disease, and for careful evaluation of the effects of duration and latency.